A growing body of evidence has convincingly argued that iPS cells contain numerous abnormalities at the genetic and epigenetic levels. Often these changes have links to the machinery in cells that is responsible for cancer. As a result, many in the stem cell field have raised the notion that iPS cells may never be able to be made in such a way that they could be used clinically.

Three new papers in tomorrow’s issue of Nature solidify these concerns and indicate beyond any reasonable doubt that iPS cells frequently contain potentially oncogenic abnormalities.

The first paper, lead by Timo Otonkoski, demonstrates that iPS cells have far more copy number variations (CNVs) in their genomes than do the parental fibroblasts from which they were made and than do ES cells. What does this mean? The high rate of CNVs in iPS cells indicates that their genomic integrity is compromised. The authors also found that this genomic instability results in iPS cell cultures being genetically heterogeneous, meaning that in a given, individual culture of iPS cells, the cells can be quite different from each other.

The second paper discovered that iPS cells have a very high rate of mutations in the coding regions of genes. Disturbingly, most of these coding mutations were in genes that are causative for cancer. Each individual iPS cell was predicted to have 6 such mutations. A table of the mutated genes can be found here.

The third paper demonstrates that iPS cells have abnormal epigenomes as has been previously observed.

What do these papers tell us?

First, as we have blogged before, iPS cells are not going to replace ES cells. It is simply not going to happen. This doesn’t mean that iPS cells are not useful. They have tremendous power for disease modeling and even if they are not as similar to ES cells as once hoped, it is still possible that iPS cells may have clinical uses that are both powerful and safe, but safety is a key point that must be resolved.

Second, these 3 new papers are simply the latest in a serious raising serious concerns about the safety of iPS cells for potential clinical use. As we blogged before (see The Inside Scoop on iPS cells in 2011), previously published papers have already established that iPS cells contain mutations and epigenetic changes.

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